Treatment of hyperkinetic conditions with caffeine

ABSTRACT

The conditions of hyperkinesis are alleviated by administering an effective amount of caffeine to subjects exhibiting such conditions.

United States Patent Biscardi Feb. 4, 1975 TREATMENT OF HYPERKINETICCONDITIONS WITH CAFFEINE [56] References Cited [75] Inventor: SalvatoreF. Biscardi, Cornwall, OTHER PUBLICATIONS Grollman, Pharmacology &Therapeutics, 6th Ed. [73] Assignee: General Foods Corporation, WhitePlains, NY. Primary Examiner-Stanley J. Friedman [22] Filed 1974Attorney, Agent, or Firm-Bruno P. Struzzi; Daniel J. [21] Appl. No.:435,902 Donovan; William J. Speranza Related U.S. Application Data [63]Continuation of Ser. No. 236,239, March 20, 1972, [57] ABSTRACTabandoned. The conditions of hyperkinesis are alleviated byadministering an effective amount of caffeine to subjects [52] U.S. Cl.424/253 exhibiting such conditions. [51] Int. Cl A6lk 27/00 [58] Fieldof Search 424/253 4 Drawmgs I TREATMENT OF HYPERKINETIC CONDITIONS WITHCAFFEINE This is a continuation, of application Ser. No. 236,239, filedMar. 20, 1972, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to the treatment ofconditions associated with the hyperkinetic syndrome and moreparticularly to the treatment of the conditions of hyperkinesis andother behavioral disorders interrelated with such conditions.

The hyperkinetic syndrome is due to minimal brain damage which mayresult from a variety of causes during the prenatal period, childbirthor early infancy. Children exhibiting such symptoms are generallyhyper-active, and have short attention spans. Their actions are oftenconsidered irrelevant and without clear direction. The restlessness,impulsiveness and garrulousness of these children disrupts disciplineboth in the home and in the classroom, and they are often regarded bytheir peers and by adults as spoiled, ill-mannered, and uncoordinated.Although the hyperkinetic child is often of average or above averageintellegence, he is usually below average in schoolwork performance,because of poor concentration and impaired motor memory and speechfunctions.

Hyperkinesis is a nervous system disorder in children and adolescentswhich is estimated to effect about 4 percent of the school population.It is a sub-group of the learning disorders in children, problems whichmay effect over of the school population. A condition which is closelyinterrelated with such behavioral problems is dyslexia, attributed morespecifically to reading disorders in children.

The conditions of hyperkinesis are also generally recognized as one ofthe important neurological dysfunctions associated with cerebral palsiedchildren. Research has shown that alleviating hyperkinetic behavior incerebral palsied children has an extremely beneficial effect by allowingthe child to overcome these behavior symptoms that may interfer with hisability to accept therapy.

Therapy in alleviating hyperkinetic conditions in children is aimed atcontrolling motor hyper-activity which results in improvement inattention, memory, perception and coordination. Surprisingly, however,sedative drugs have been found to be ineffective in calming thesechildren and, in fact, actually cause extreme agitation in hyperkineticchildren. Quite to the contrary, stimulant drugs such as amphetamines,have been found to be effective in producing a calming effect in nearly85 percent of these patients. In the treatment of cerebral palsiedchildren, the use of amphetamines have been shown also to be effective,primarily due to its ability to alleviate conditions of the hyperkineticimpulse disorder.

The amphetamines and other stimulants used currently in the treatment ofhyperkinetic condition, however, have appreciable undesirable sideeffects. Almost percent of children treated with such stimulantsdemonstrate anorexia, irritability and insomnia. Further, the underlyingfears associated with the use of drugs such as amphetamines hasgenerally hampered their effectiveness in the treatment of disorders inchildren.

It would be desirable, then, to achieve a calming effect in hyperkineticpatients through the use of a compound which does not produce anyundesirable amphetamine-like side effects.

SUMMARY OF THE INVENTION It has been found that the administration ofeffective amounts of caffeine to a patient displaying hyperkineticconditions or the related conditions of dyslexia is effective inalleviating such conditions and does not produce any appreciableundesirable side effects at the dosage levels at which it is effective.

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, amphetamines.stimulant drugs, which one would normally predict would increasehyper-activity have been found to result in a calming effect inhyperkinetic children. Theories advanced to explain this resultgenerally hold that hyperkinetic children have a defect in the pathwaysfor sensory input into the brain. The children then are hyperactive toincrease the number of sensory stimuli produced, and, therefore, toincrease to higher levels the number ofsensory stimuli reaching thebrain. Amphetamines increase the neural activity so that moreexperienced stimuli are actually perceived and less hyperactivity isnecessary to produce higher levels of stimuli reaching the brain.

In order to determine the effectiveness of therapy in alleviatingconditions of hyperkinesis in children, tests are normally conducted tomeasure the activity of a hyperkinetic child his concentration, and hisresponse to stimuli as measured by electroencephalogram techniques.

A clinical investigation was undertaken to determine the effect ofcaffeine treatment on patients exhibiting hyperkinetic conditions and toevaluate the treatment for undesirable side effects. The subjects forthis study were seventeen children previously diagnosed as beinghyperkinetic. Their ages ranged from 8 years to 11 years. All subjectsreceived three treatments, in counter-balanced order: placebo (control),a low dose of caffeine, and a high dose of caffeine. The low dose wasapproximately 3 mg/kg, and the high dose was approximately 6 mg/kg. Theactual dosage ranged from to mg. per subject. The mean weight of thesubjects was 28.5 kg.

The children tested were randomly assigned to six possible orders of thethree treatments. The children received the coded tablets, double-blind,one hour before the start of testing which lasted for approximately onehour.

The following tests were administered in a fixed order:

1. Continuous Performance Test.

This ten-minute test required the child'to monitor a display of fivebuttons, four of which present two patterns (horizontal or verticalstripe) in two colors (red or blue). The display changes every 1.6seconds, and the child presses a center buttonwhenever he sees thered-vertical appear. The target item appears about fifty times, andthere a total of 300 trials. Errors of omission and errors of commissionare recorded automatically on counters.

The mean errors of commission and omission for the three treatments areshown in Table l.

The figures presented in Table I represent statistically analyzedaverages of the fixed orders of treatment. As can be seen from thefigures, the high dose treatment produced the fewest errors ofcommission, that is, the fewest number of errors caused by the childpressing the button when in fact the red vertical had not appeared, andalso produced the fewest errors of omission, that is, errors caused bythe child not pressing the button when a red vertical had appeared. Theplacebo condition, as can be seen from Table I, produced the highestnumber of errors of both omission and commission, with a low dose ofcaffeine intermediate. Since the hyperkinetic child often displays poorconcentration and impaired motor functions, the results of thecontinuous performance test indicate a significant beneficial effectthrough the use of caffeine. Further, the test indicates that theeffects obtained appear to be dose related.

2. Activity Measurement.

While the child is taking the continuous performance test he sits in achair which records activity (seat movement. seat rotation, or footmovement). The sum of these measures of fidgeting constitute an overallmeasure of activity, the results of which are shown in Table ll.

The results of Table ll again indicate a beneficial effect in thereduction of hyper-activity through the use of caffeine. The highestactivity is seen to occur for the placebo treatment, and the lowest forthe highdose of' caffeine. 3. Visual Cortical Evoked Response.

This is the measure of responses, as measured on an electroencephalogram(EEG), obtained from left and right occipital, and left and rightparietal areas of the scalp. Experiments have shown that deflectioninthe EEG and also the amplitude of certain of the waves recorded areindicative of increased activity normally found in hyperkineticchildren. The stimuli to which responses were averaged consisted offlashes presented at 1.6 second intervals. Randomly interpersed with thebright flashes were dim flashes to which the subject had to respond bypressing a telegraph key. Analysis of the wave forms recorded on the EEGshowed that large positive peaks normally found in the hyperkineticchildren are significantly smaller when 'the children are treated withcaffeine. Again, the effect appears to be dose related in that the highdose of caffeine produced the smallest possible peaks and the low doseintermediate between those obtained for the placebo and the high dose.

At the close of the testing period the children were found to havesuffered no adverse effects from the caffeine treatment as indicatedboth by self and parental reports.

The overall results of the tests indicate a beneficial effect on thetreatment of the hyperkinetic syndrome through drug therapy employingcaffeine. As previously mentioned, this finding is useful in treatingchildren whose problems are solely hyperkinetic activity or its relatedreading disorder, dyslexia, and also for treatment ofthe hyperkineticconditions found to be prominent in more complex behavioral disorderssuch as cerebral palsy.

Administration to the subject of an amount of caffeine effective toallay hyperkinetic conditions may be accomplished in a variety ofmethods. The caffeine may be incorporated within an edible, inertpharmaceutical carrier, or may be incorporated directly into afoodstuff. Preferably, the foodstuff should be one which is readilyacceptable to children and which does not mask the effects of thecaffeine treatment. Examples of such foodstuffs would be beverages orbeverage mixes, cereal, candy, confectionaries, and the like. Thefoodstuffs are formulated such that the amount of caffeine within thefoodstuff is sufficient for administering the required amount ofcaffeine which is effective in alleviating hyperkinetic conditions.Thus, for example, a beverage drink may be prepared such that ingestionofa normal amount of the drink, say 8 ounces, provides an amount ofcaffeine effective to alleviate the hyperkinetic conditions.

The amount of caffeine administered is that amount which is effective toproduce the desired alleviation of hyperkinetic conditions in subjectsexhibiting such conditions. The administration is generally as needed. Apreferred level for administering caffeine is amounts of at least about3 mg/kg of body weight of the subject.

Experimentation has shown that the effects imparted by the caffeine aredose related, and, therefore, upper limits on the dosage amount ofcaffeine employed are subject solely to considerations of the appearanceof side effects in the subject. As previously mentioned, dosage levelsof 6 mg/kg have been found to be effective without producing anyappreciable undesirable side effects.

We Claim:

1. A method of alleviating hyperkinetic conditions, comprising orallyadministering to a subject exhibiting said conditions a dosage amount ofcaffeine effective to alleviate said conditions.

2. The method according to claim 1 wherein said dosage amount ofcaffeine is from about three milligrams to about six milligrams for eachkilogram of body weight of said subject.

3. The method of claim 2 wherein said dosage amount of caffeine isincorporated within an edible, inert pharmaceutical carrier.

4. The method of claim 2 wherein said dosage amount of caffeine is addedto a foodstuff.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,864,489 Dated February 4, 197,5

Inventoflg) Salvatore F. Biscardi It: is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

In column 3, Table I, opposite "Placebo" and under heading "Errors ofCommission," change "16.523" to 16.528

Signed and sealed this 15th day of July 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officerand Trademarks

1. A METHOD OF ALLEVIATING HYPERKINETIC CONDITIONS, COMPRISING ORALLYADMINISTERING TO A SUBJECT EXHIBITING SAID CONDITIONS A DOSAGE AMOUNT OFCAFFEINE EFFECTIVE TO ALLEVIATE SAID CONDITIONS.
 2. The method accordingto claim 1 wherein said dosage amount of caffeine is from about threemilligrams to about six milligrams for each kilogram of body weight ofsaid subject.
 3. The method of claim 2 wherein said dosage amount ofcaffeine is incorporated within an edible, inert pharmaceutical carrier.4. The method of claim 2 wherein said dosage amount of caffeine is addedto a foodstuff.
 5. A foodstuff containing an added amount of caffeineeffective to alleviate hyperkinetic conditions in a subject exhibitingsuch conditions.
 6. A foodstuff according to claim 5 wherein said amountof caffeine in said foodstuff is sufficient for administering to saidsubject about three milligrams to about six milligrams of caffeine foreach kilogram of body weight of said subject.
 7. The foodstuff of claim6 wherein said foodstuff is selected from the group consisting ofcereals and beverages.
 8. The foodstuff of claim 5 wherein saidfoodstuff is selected from the group consisting of cereals andbeverages.